The CB1 receptor (cannabinoid receptor-1, gene name Cnr 1) is a Gi-coupled G-Protein Receptor that is widely expressed in the CNS and peripheral nervous system. Agonist stimulation of CB1 receptors leads to inhibition of adenyly cyclase activity and activation of mitogen-activated protein (MAP) kinase. CB1 receptors are highly conserved between human, mouse and rat.
CB1 receptors are among the most abundant and widely distributed G protein-coupled receptors in the mammalian brain. They are also found in peripheral tissues including adipose, liver, muscle and the gastrointestinal tract.
Endogenous agonists of the CB1 receptor can comprise anandamide and 2-arachidonoyl glycerol. Exogenous agonists can comprise Δ9-tetrahydrocannabinol. Small molecule antagonists or inverse agonists (used interchangeably) such as rimonabant or taranabant have been shown to reduce body weight and improve metabolic parameters, e.g. reduced plasma glucose and insulin levels.
Unfortunately, such small molecule antagonists have also been shown to have adverse CNS effects. For example, it has been reported that rimonabant, a CB1 small molecule receptor antagonist/inverse agonist which binds to CB1 receptors increased the incidence of anxiety, depression, and suicidal ideation in multiple clinical trials (NDA 21-888 FDA Briefing Document, Jun. 13, 2007)
Small molecule antagonists with poor brain penetration (for example AM6545 and JD5037) have been reported to reduce food intake and body weight gain and improve multiple metabolic parameters in mice (Tam et al, J. Clin. Invest. 120:2953-66, 2010; Tam et al Cell Metab 16:1-13, 2012). Additional peripherally-restricted small molecules have been described (US2011/0144157)
It is possible that the positive metabolic effects of CB1 antagonists can be mediated by peripheral receptors. Therefore, a peripherally-acting large molecule may be efficacious and safer than failed small molecule therapies.